Blends of oligopeptide terminal polyisobutylene or polystyrene

Various blends of polymers are disclosed, comprising oligopeptide functionalised polymers such as polyisobutylene and polystyrene. Mono-functionalised and di-functionalised polymers (each containing 0 to 5 peptide units beyond its terminal amide group) may be blended with each other and / or with non-functionalised polymers to produce blended compositions. Such compositions are of use, for example, in vibrations dampers. Certain blends also exhibit self-healing properties.

Synthesis, structural characterization and applications of hyperbranched polymers based on L-lysine

Markus Scholl

L-lysine is an essential a-amino acid and a necessary building block for all proteins in the body. As an essential amino acid, L-lysine is not synthesized by humans or animals. Industrially produced L-lysine has therefore a big market as food additive, e.g. in pig food. In the body, L-lysine plays a major role in calcium absorption, building muscle proteins, recovering from surgery or sports injuries, and the body's production of hormones, enzymes, and antibodies.1 From a chemical point of view, L-lysine is an AB2 building block that contains two amino groups and one carboxylic acid group, which makes it an interesting monomer for the synthesis of dendrimers and hyperbranched polymers. L-lysine indeed has been extensively used to synthesize dendrimers2-4 or conjugates of dendrimers and linear polymers.5,6 These dendrimers and linear-dendritic hybrid architectures have attracted interest for various medical applications, including gene delivery,3,6-8 as drug carriers,9 for the development of multiple antigen peptide systems,10,11 and as magnetic resonance imaging agents.12 The drawback of these dendrimers and linear-dendritic hybrid architectures is their time consuming synthesis and their expensive large scale production. This thesis evaluates the feasibility of L-lysine as a monomer to synthesize hyperbranched polymers and investigates the potential of these materials as encapsulation agents and for various biomedical applications. As the hyperbranched polylysines are prepared in a single step and can be produced conveniently at a large scale, they may offer an interesting alternative to their widely used dendritic analogues. Including this introduction, this thesis consists of 8 chapters, which are briefly described below. Chapter 2 gives a general overview of dendritic and hyperbranched polymers build up of amide bonds. Their synthesis and applications in medicine and catalysis as well as their self-assembling and encapsulation properties will be discussed. Chapter 3 reports on the synthesis of hyperbranched polylysines via the thermal polymerization of L-lysine hydrochloride.13 Different catalysts were investigated to improve the reaction kinetics. The structure of the polymers was determined by 1H-NMR spectroscopy, and the degree of branching and the average number of branches were calculated. Chapter 4 will discuss the feasibility of different approaches to control polymer architecture during the thermal hyperbranched polymerization of L-lysine hydrochloride.14 The reactivity of the more reactive ε-NH2 group was modulated by introducing temporary protective groups. The distribution of structural units was analyzed by 1H-NMR spectroscopy and the degree of branching and the average number of branches were calculated. Chapter 5 will describe the dilute solution and solid state structure of hyperbranched polylysines and polyelectrolyte complexes generated from hyperbranched polylysine and various anionic, sodium alkyl sulfate surfactants.15 Structural models for the obtained liquid crystalline phases will be proposed. Chapter 6 will show some preliminary results of the end group modification of hyperbranched polylysine with different hydrophilic and hydrophobic agents. The feasibility of these hydrophobically modified hyperbranched polylysines to encapsulate hydrophilic dyes and transfer them from aqueous to organic media has been investigated. Chapter 7 provides a first insight into the biological properties of hyperbranched polylysine. In this chapter the results from preliminary cytotoxicity and cellular uptake experiments will be discussed. Chapter 8 will give a short summary of the work done in this thesis and an outlook. References Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. Denkewalter, R. G.; Kolc, J. F.; Lukasavage, W. J. In U.S. Pat. 4289872; Allied Corporation, 1981; Chem. Abstr. 1981, 102, 79324. Ohsaki, M.; Okuda, T.; Wada, A.; Hirayama, T.; Niidome, T.; Aoyagi, H. Bioconjugate Chem. 2002, 13, 510-517. Driffield, M.; Goodall, D. M.; Smith, D. K. Org. Biomol. Chem. 2003, 1, 2612-2620. Lübbert, A.; Nguyen, T. Q.; Sun, F.; Sheiko, S. S.; Klok, H.-A. Macromolecules 2005, 38, 2064-2071. Choi, J. S.; Joo, D. K.; Kim, C. H.; Kim, K.; Park, J. S. J. Am. Chem. Soc. 2000, 122, 474-480. Vlasov, G. P.; Korol'kov, V. I.; Pankova, G. A.; Tarasenko, I. I.; Baranov, A. N.; Glazkov, P. B.; Kiselev, A. V.; Ostapenko, O. V.; Lesina, E. A.; Baranov, V. S. Russ. J. Bioorg. Chem. 2004, 30, 12-20. Choi, J. S.; Lee, E. J.; Choi, Y. H.; Jeong, Y. J.; Park, J. S. Bioconjugate Chem. 1999, 10, 62-65. Sakthivel, T.; Toth, I.; Florence, A. T. Pharm. Res. 1998, 15, 776-782. Tam, J. P. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 5409-5413. Pessi, A.; Bianchi, E.; Bonelli, F.; Chiappinelli, L. J. Chem. Soc., Chem. Commun. 1990, 8-9. Nicolle, G. M.; Tóth, E.; Schmitt-Willich, H.; Radüchel, B.; Merbach, A. E. Chem. Eur. J. 2002, 8, 1040-1048. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. J. Polym. Sci. Part A Polym. Chem. 2007, 45, 5494-5508. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. Macromolecules 2007, 40, 5726-5734. Canilho, N.; Scholl, M.; Mezzenga, R.; Klok, H.-A. Macromolecules 2007, 40, 8374-8383.

EPFL2007

Synthesis of sequence-defined oligomers and polymers

Nadja Franz

The preparation of synthetic polymers with exact control over chain length and monomer sequence is one of the long-standing challenges in polymer science. Nature perfectly masters the synthesis of high molecular weight, perfectly monodisperse polypeptides (proteins), which outperform synthetic polymers, both in terms of structural complexity as well as with respect to functional properties. The availability of synthetic strategies that would allow the preparation of polymers with a defined primary structure and chain length, and consequently, a controlled folding behavior in solution, may lead to polymeric materials with new or improved properties and functions. Over the past decades, several "living" or controlled polymerization techniques have been developed, which significantly enhanced the ability to control chain length, monomer sequence and composition: nowadays, synthetic polymers can be prepared with relatively narrow chain length distributions. However, in spite of all these advances, these methods still do not allow the preparation of polymers with perfectly uniform chain lengths and strictly defined monomer sequences, which would represent the synthetic counterpart of the proteins produced by Nature. An alternative approach towards precisely-defined polymers relies on multistep synthetic protocols and has already allowed the successful preparation of a wide variety of uniform oligomers. The synthesis of monodisperse oligomers with the propensity to fold (so called "foldamers") provides a useful stepping-stone for the synthesis and establishment of structure-property relationships with the corresponding higher molecular weight polymers. This Thesis describes the synthesis of oligomers and polymers with strictly defined monomer sequences, with the ultimate aim to direct and control their folding behavior, supramolecular organization and properties in solution. The design of the proposed oligomers/polymers is based on the principle of hydrophilic/hydrophobic patterning, which is a well-established and powerful strategy to guide secondary structure formation of both natural as well as non-natural oligomers and polymers. For example, alternating sequences of hydrophilic and hydrophobic residues are expected to lead to β-sheet type secondary structures. Three approaches have thus been investigated to obtain strictly alternating hydrophilic/hydrophobic oligomers and polymers. The different synthetic strategies that have been used for the preparation of these non-natural oligomers and polymers are reviewed in Chapter 1. The first approach explores the feasibility for the synthesis of uniform, sequence-defined, hydrophilic/hydrophobic patterned oligo(α-hydroxy acid)s (Chapter 2). This strategy is based on post-modification of a reactive oligoester scaffold composed of an alternating sequence of hydrophobic ((2S)-2-hydroxy-4-methylpentanoic acid) and masked hydrophilic ((2S)-2-hydroxypent-4-enoic acid) α-hydroxy acids. In a subsequent post-modification step, the allyl side chains could be quantitatively modified via free-radical addition of different ω-functional thiols to afford hydrophilic/hydrophobic patterned oligoesters. This synthetic route provides an interesting method to generate libraries of foldamers with identical chain length and monomer sequence but different side chain functionalities. The second approach relies on the preparation of the corresponding oligopeptide analogues (Chapter 3). Alternating hydrophilic/hydrophobic patterned peptide foldamers were obtained via post-modification of a reactive peptide precursor, synthesized via solid phase peptide synthesis (SPPS). The peptide scaffolds consisted of an alternating sequence of L-leucine and L-allylglycine residues. Thiol-ene coupling chemistry allowed the post-modification of the allylglycine residues with cysteamine hydrochloride, thioglycolic acid, 1-thioglycerol and 2,3,4,6-tetrα-O-acetyl-thio-β-d-glucopyranose. The dilute solution folding properties of the cysteamine and thioglycolic acid post-modified octapeptides were studied by circular dichroism (CD) spectroscopy. In agreement with the alternating hydrophilic/hydrophobic patterned primary structure, these peptides were found to adopt a β-sheet secondary structure in basic and acidic aqueous media, respectively. The preparation of high molecular weight polydepsipeptides, which are structurally related to oligoesters and oligopeptides, is discussed in Chapter 4. Polydepsipeptides were obtained via tin(II) 2-ethylhexanoate catalyzed ring-opening polymerization (ROP) of morpholine-2,5-dione derivatives. To allow flexibility in the choice of the side chain functional groups, morpholine-2,5-dione derivatives were constructed using L-allylglycine. Introduction of diverse functional groups in the side chains was achieved via radical addition of ω-functional thiols. This approach can be regarded as a convenient and rapid method for the synthesis of high molecular weight functional polymers, with strictly alternating monomer sequences.

EPFL2009

Synthesis of sequence-defined oligomers and polymers

Nadja Franz

EPFL2009

Synthesis, structural characterization and applications of hyperbranched polymers based on L-lysine

Markus Scholl

EPFL2007